Pyrroloquinoline quinone (hereinafter sometimes referred to as “PQQ”) has been proposed as a possible new vitamin (see, for example, Non-patent document 1), and has attracted much attention as a useful material for dietary supplements, cosmetics, etc. Moreover, PQQ is present not only in bacteria but also in eukaryotic molds and yeasts and plays an important role as a cofactor. Also, PQQ has been found to have many physiological activities such as cell growth-promoting activity, anti-cataract activity, hepatic disease-preventing and therapeutic activity, wound healing activity, antiallergic activity, reverse transcriptase-inhibiting activity and glyoxalase I-inhibiting activity—anticancer activity, nerve fiber regeneration, and the like. It is known in the art that the higher crystallinity provides the chemical stability and the longer shelf life, and consequently an agent having such higher crystallinity is less in need of stabilizing, has a longer shelf life, and has the potential to be provided in the form of relatively simple packaging.
PQQ can be obtained by subjecting PQQ obtained by methodologies such as organic chemical syntheses (Non-patent document 2) or fermentation processes (Patent document 1) to chromatography, concentrating the PQQ fraction in the effluent and adding an organic solvent to the fraction to crystallize PQQ by crystallization (Patent document 2), followed by drying the crystallized PQQ. An alkali metal salt of PQQ may be obtained by precipitation from the corresponding aqueous solution by adding an alcohol to the solution to reduce the solubility of the salt. The alkali metal salt, however, does not have high crystallinity. In addition, this method involves using an organic solvent that is expensive, flammable and costly in terms of waste disposal. Thus, a method without using such solvent is sought after. Also, in Non-patent document 2, a method for producing the disodium salt of PQQ in crystal form is provided, but this method has low productivity and is not industrially useful. Moreover, calcium ions are important as nutritional components and desirably ingested simultaneously with pyrroloquinoline. Any specific method for producing a calcium salt of PQQ, however, has not been reported so far.
Although an alkaline-earth metal salt of PQQ as well as an alkaline metal salt of PQQ is disclosed in Patent document 2, there is no working example of such an alkaline-earth metal salt. Moreover, this method involves crystallization by using an organic solvent, resulting in costly facilities for handling flammable substances and waste water. Moreover, alkali metal salts of PQQ are soluble in water, and readily react with amine, carbonyl and reducing compounds, in particular in such a moisture-containing environment where these salts are dissolved. The alkali metal salts are therefore required to have a low solubility in water in order to increase their stability. It is desired that PQQ is readily absorbed when administered as food or drugs.
Furthermore, PQQ and salts thereof are often obtained in red or dark red color. These colors are known to be unique to PQQ, and heightened when PQQ is mixed with food or drugs, which may result in failure to adjust the color of the mixture to an intended target color. In particular, the color of PQQ may present a difficulty in designing a target color in food products in which palatability is important. Therefore, the color of PQQ is desirably close to white. The color of PQQ may look white by coating or mixing with other components. However, addition of non-essential components has a disadvantage of a decreased level of freedom in designing the ingredients of food or drugs. Also, in the case of coating, the coated PQQ is required to have the same functionalities as the original PQQ or to return to the original PQQ. Alternatively, it is envisaged that the color is changed by chemical modification through organic synthesis, which needs many organic solvents and highly toxic reagents.
In addition, since PQQ is highly reactive, it is desirably in the form of solid in the place where it comes in contact with food, and of liquid in the intestines where it is absorbed.